This study aims to investigate the effects and mechanisms of parathyroid hormone [1–34] (PTH1-34) on TNF-α-stimulated mice chondrocytes, as well as cartilage from a meniscus injury induced osteoarthritis (MIO) mice model. The C57BL/6J mice received medial meniscectomy, and then administrated with PTH1-34. The results showed that PTH1-34 administration decreased secondary allodynia and the pain-related transcripts. The IHC, ELISA, Micro-CT imaging and histopathology analysis revealed the significantly improved subchondral plate thickness and bone porosity, the reduced pro-inflammatory cytokines in serum and joint fluid. In vitro, mice chondrocyte was treated with TNF-α or co-cultured with synovial cells. The results showed that TNF-α markedly upregulated the MMP13 expression, and the ERK1/2, NF-κB or PI3K signaling pathway inhibitors could reverse the induction effect of TNF-α on expression of MMP13 in chondrocytes. PTH1-34 alone has no effect on the expression of MMP13 and NF-κB signaling pathways, but the PTH1-34 could reverse the induction effect of TNF-α on MMP13 expression and NF-κB signaling pathway activation in chondrocytes. In addition, PTH1-34 administration inhibited the expression of TNF-α and MMP13, and chondrocyte viability, while the PKA repressor reversed the effect of PTH1-34 in chondrocytes co-cultured with synovial cells. In conclusion, PTH1-34 has an obvious analgesic and anti-inflammatory effect, inhibits the matrix synthesis and alleviates the progression of osteoarthritis. In vitro, PTH1-34 inhibited TNF-α expression and antagonized TNF-α-induced MMP13 expression via the PKA pathway and the NF-κB signaling pathways, respectively.

本研究旨在探讨甲状旁腺激素 [1-34] (PTH1-34) 对 TNF-α 刺激的小鼠软骨细胞以及半月板损伤诱导骨关节炎 (MIO) 小鼠模型软骨的影响和机制。 C57BL/6J小鼠接受内侧半月板切除术，然后给予PTH1-34。结果表明，PTH1-34 给药可减少继发性异常性疼痛和疼痛相关转录本。 IHC、ELISA、Micro-CT 成像和组织病理学分析显示，软骨下板厚度和骨孔隙度显着改善，血清和关节液中促炎细胞因子减少。在体外，用 TNF-α 处理小鼠软骨细胞或与滑膜细胞共培养。结果显示，TNF-α显着上调MMP13表达，ERK1/2、NF-κB或PI3K信号通路抑制剂可逆转TNF-α对软骨细胞MMP13表达的诱导作用。单独使用PTH1-34对MMP13和NF-κB信号通路的表达没有影响，但PTH1-34可以逆转TNF-α对软骨细胞MMP13表达和NF-κB信号通路激活的诱导作用。此外，PTH1-34 给药抑制 TNF-α 和 MMP13 的表达以及软骨细胞活力，而 PKA 阻遏物逆转了 PTH1-34 在与滑膜细胞共培养的软骨细胞中的作用。综上所述，PTH1-34具有明显的镇痛抗炎作用，抑制基质合成，减缓骨关节炎的进展。在体外，PTH1-34分别通过PKA通路和NF-κB信号通路抑制TNF-α表达并拮抗TNF-α诱导的MMP13表达。